title: Population pharmacokinetics of tacrolimus in adult kidney transplant patients: impact of CYP3A5 genotype on starting dose.
abstract: OBJECTIVE
  The aims of this study were to develop a population pharmacokinetic model of tacrolimus in adult kidney transplant recipients, to use this model to compare cytochrome P450 3A5 (CYP3A5) genotype-based initial dosing of tacrolimus with standard per-kilogram-based dosing, and to predict the best starting dose of tacrolimus based on patient genotype to achieve a trough concentration between 6 and 10 µg/L by day 5 posttransplantation.
  
  
  METHODS
  Population analysis was performed using the software program NONMEM. Tacrolimus dosing regimens were compared by predicting tacrolimus trough concentrations in a simulated data set by running NONMEM with population parameters fixed at the final model estimates. Data from 173 patients with 1554 tacrolimus concentration-time measurements were modeled.
  
  
  RESULTS
  Tacrolimus disposition was well described by a 2-compartment model with first-order elimination and first-order absorption after a lag time. Patient CYP3A5 genotype (rs776746), weight, hematocrit, and postoperative day were identified as significant covariates effecting tacrolimus apparent oral clearance (CL/F), with higher CL/F in CYP3A5*1 allele carriers, heavier patients, patients with low hematocrit, and in the immediate posttransplantation period. Typical population estimates for tacrolimus CL/F in CYP3A5*1 allele carriers and noncarriers were 40.8 and 25.5 L/h, respectively.
  
  
  CONCLUSIONS
  In patients carrying the CYP3A5*1 allele, a per-kilogram dose of 0.075 mg/kg twice daily seemed too much low with approximately 65% of simulated subjects predicted to achieve a trough below 6 µg/L at day 5 posttransplantation. To reduce the risk of under immunosuppression in the immediate posttransplantation period, carriers of a CYP3A5*1 allele are likely to benefit from a tacrolimus starting dose of either 10 mg or 0.115 mg/kg twice daily.
authors.affiliation: *School of Pharmacy, University of Queensland, Brisbane, Australia; †Department of Pharmacology, Aarhus University, Aarhus, Denmark; and ‡Department of Nephrology, University of Queensland at the Princess Alexandra Hospital, Brisbane, Australia.
authors.forename: Troels K
authors.initials: TK
authors.lastname: Bergmann
authors.forename: Stefanie
authors.initials: S
authors.lastname: Hennig
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Barraclough
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Isbel
authors.forename: Christine E
authors.initials: CE
authors.lastname: Staatz
mesh_terms: D000328:Adult; D000483:Alleles; D003198:Computer Simulation; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D017711:Nonlinear Dynamics; D011446:Prospective Studies; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus